Long-term changes in synaptic efficacy are essential for neuronal development, learning, memory formation, and pathological states of neuronal excitability. There is good evidence that synaptic transmission can be either enhanced (LTP) or depressed (LTD). Although in most excitatory synapses studied this bidirectional modification is triggered by postsynaptic calcium rises and expressed by modification in the number of glutamate receptors, it is unclear how bidirectional changes occur at synapses in which plasticity is due to a persistent modification in transmitter release. By using a combination of electrophysiological techniques, Ca2+ imaging, and genetically engineered mice, we will study mechanisms of LTD at mossy fiber to CA3 pyramidal cell synapses in the hippocampus where a great deal is known about the mechanisms of presynaptic LTP but little about LTD. We will also extend our study to hippocampal inhibitory synapses where we found a presynaptic form of long-term plasticity that is triggered by endocannabinoids. Our goal will be to identify mechanisms of bidirectional changes common to inhibitory and excitatory synapses. We expect to gain a better understanding of the molecular and cellular basis of cognitive functions as well as neurological and behavioral disorders involving alterations of neurotransmitter release, such as dementia, epilepsy and drug addiction.